Comparison of estrogenic components used for hormonal contraception.

Attempts have been made over the years to replace ethinyl estradiol (EE) in combined oral contraceptives (COCs) with the less potent natural estrogen estradiol (E2), or its prodrug, E2 valerate (E2V), to improve their safety and tolerability. Recently, a COC incorporating a novel weak natural estrogen, estetrol (E4), combined with drospirenone, has become available. We present a comparative analysis of the three prevailing estrogens used in COCs, focusing on their structure-function relationships, receptor-binding affinity, potency, metabolism, pharmacokinetic parameters, and pharmacodynamics. The binding affinity of EE to estrogen receptor (ER)α is twice that of E2, whereas its affinity for ERß is about one-half that of E2. E4 has a lower binding affinity for the ERs than E2. The high potency of EE is notable in its dramatic increase in estrogen-sensitive hepatic globulins and coagulation factors. EE and E2 undergo extensive and comparable metabolism, while E4 produces only a very limited number of metabolites. E4 has the highest bioavailability among the three estrogens, with E2 having <5%. Studies demonstrate consistent ovulation inhibition, although a higher dose of E4 (15 mg) in COCs is required to achieve follicular suppression compared to E2 (1-3 mg) and EE (0.01-0.035 mg). E2 and E4 in COCs may be less stimulatory of coagulant proteins than EE. Studies with E2/dienogest suggest a comparable risk of venous thromboembolism to EE/levonorgestrel, while data assessing risk with an E4-based COC are insufficient. Nevertheless, the E4-based formulation shows promise as a potential alternative to EE and E2 due to its lower potency and possibly fewer side effects.

Family Planning, Fertility, and Medical School: A Survey of Students' Plans and Perceptions of Institutional Support.

Background Deciding when to pursue parenthood can be difficult for medical trainees and infertility is more common in the physician population. However, few studies have examined the views of very early career trainees. The goal of this study was to assess premedical and medical student plans for family building, knowledge of fertility, and thoughts on assisted reproductive technology, as well as institutional support for parenthood in medical school and fertility curriculum. Methods Web-based cross-sectional survey on Qualtrics distributed through social media and school organization-based networks. Responses were reported as frequency and percent and compared across subgroups of population with χ2 tests. Results The study had a total of 605 premedical and medical students respondents. Most students (78%) do not have children but plan to have children in the future. Almost two-thirds (63%) of students would consider using assisted reproductive technology. More than 80% of respondents have considered or would consider oocyte cryopreservation for themselves or their partners. A majority (95%) of students are worried about balancing parenthood and a career in medicine and about their fertility declining while they complete medical training (84%). The most frequently cited barriers to family planning during medical school and residency were: limited time off during training (84%), demands of training (82%), cost of having a child (59%), and stigma of having a child during training (45%). Less than half of medical students had formal education on infertility. Conclusions Premedical and medical students are worried about fertility declining in training and about balancing parenthood and medical careers, but gaps in knowledge and institutional support exist.

Does timing matter when initiating elagolix in a natural menstrual cycle?

OBJECTIVE: To investigate the efficacy of elagolix when administered at different time points in a menstrual cycle. DESIGN: Clinical case series. SETTING: Academic reproductive endocrinology center. PATIENTS: Ovulatory women not desiring pregnancy. INTERVENTIONS: Six doses of elagolix 200 mg were administered over 4 days, starting at 3 different points in a menstrual cycle: early follicular; late follicular; and midluteal. Serum follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol (E2), and progesterone (P) concentrations were measured at baseline, during elagolix administration, and 1 day after the last dose. Transvaginal ultrasounds were performed to monitor follicle sizes. MAIN OUTCOME MEASURES: Serum FSH, LH, E2, and P. RESULTS: Twelve women, four per group, completed the study. Subjects were 23-42 years of age. Demographics and ovarian reserve parameters were similar among participants. Elagolix suppressed FSH, LH, E2, and P when administered in the early follicular and midluteal phases but had mixed results when administered in the late follicular phase. Two participants demonstrated suppression of all four hormones. One participant ovulated, indicated by an increase in P concentration and development of a corpus luteum. A second participant did not ovulate yet demonstrated an increase in E2 concentration with growth of a dominant follicle. There were no significant differences in median percent change of hormone concentrations across study groups. CONCLUSIONS: The results of this study suggest that elagolix can suppress the hypothalamic-pituitary-ovarian axis when initiated at different points in a menstrual cycle. Optimal dosing and treatment window for consistent hormone suppression have yet to be determined. CLINICAL REGISTRATION NUMBER: NCT04060992.

Successful Vaginal Delivery after External Cephalic Version in a Woman with a Large Partial Uterine Septum.

Septate uteri have been associated with adverse pregnancy outcomes including spontaneous abortion, preterm delivery, and malpresentation. It is unclear if uterine septa are associated with infertility. Although some studies have shown improved pregnancy outcomes after septum resection, indications for resection are not well established. We describe a case of a woman with a large partial uterine septum diagnosed during workup for infertility who conceived without septum resection. Both of her subsequent pregnancies were initially breech presentations for which the patient underwent external cephalic version followed by full-term vaginal deliveries. This case adds evidence that an unresected uterine septum should not be considered a contraindication to external cephalic version.

Progestogens used in postmenopausal hormone therapy: differences in their pharmacological properties, intracellular actions, and clinical effects.

The safety of progestogens as a class has come under increased scrutiny after the publication of data from the Women's Health Initiative trial, particularly with respect to breast cancer and cardiovascular disease risk, despite the fact that only one progestogen, medroxyprogesterone acetate, was used in this study. Inconsistency in nomenclature has also caused confusion between synthetic progestogens, defined here by the term progestin, and natural progesterone. Although all progestogens by definition have progestational activity, they also have a divergent range of other properties that can translate to very different clinical effects. Endometrial protection is the primary reason for prescribing a progestogen concomitantly with postmenopausal estrogen therapy in women with a uterus, but several progestogens are known to have a range of other potentially beneficial effects, for example on the nervous and cardiovascular systems. Because women remain suspicious of the progestogen component of postmenopausal hormone therapy in the light of the Women's Health Initiative trial, practitioners should not ignore the potential benefits to their patients of some progestogens by considering them to be a single pharmacological class. There is a lack of understanding of the differences between progestins and progesterone and between individual progestins differing in their effects on the cardiovascular and nervous systems, the breast, and bone. This review elucidates the differences between the substantial number of individual progestogens employed in postmenopausal hormone therapy, including both progestins and progesterone. We conclude that these differences in chemical structure, metabolism, pharmacokinetics, affinity, potency, and efficacy via steroid receptors, intracellular action, and biological and clinical effects confirm the absence of a class effect of progestogens.

Premenstrual syndrome and premenstrual dysphoric disorder: quality of life and burden of illness.

Premenstrual symptoms are distressing for up to 20% of reproductive-aged women and are associated with impairment in interpersonal or workplace functioning for at least 3-8%. Typical symptoms of premenstrual syndrome and the severe form, premenstrual dysphoric disorder, include irritability, anger, mood swings, depression, tension/anxiety, abdominal bloating, breast pain and fatigue. The symptoms recur monthly and last for an average of 6 days per month for the majority of the reproductive years. For women with premenstrual dysphoric disorder, the symptoms can be as disabling as major depressive disorder. It has been estimated that affected women experience almost 3000 days of severe symptoms during the reproductive years. Until two decades ago, there were no effective treatments for severe premenstrual syndrome. Even in 2000, almost three-quarters of women in the USA with premenstrual disorders either did not seek help or sought treatment unsuccessfully from at least three clinicians for over 5 years. This review will focus on the epidemiology, diagnosis, treatment outcomes, quality of life and burden of illness for premenstrual disorders.

Drospirenone/ethinyl estradiol.

Drospirenone 3 mg/ethinyl estradiol 20 microg (24/4) is a new unique oral contraceptive formulation that combines in a novel dosing regimen the lowest dosage of ethinyl estradiol commonly used today with drospirenone, an innovative progestin. Drospirenone is a compound closely resembling progesterone, but with the antimineralocorticoid and antiandrogenic properties of a related therapeutic agent, the diuretic, antihypertensive and androgen receptor antagonist, 17alpha-spironolactone. The prolongation of hormonally active pills in the monthly drospirenone/ethinyl estradiol cycle from 21 days to 24 days, followed by 4 days of inactive pills, is an interesting variant of the recently developed extended pill regimens (1). Recent contraceptive research has focused on improving side effect profiles and providing noncontraceptive health and lifestyle advantages. Many of these benefits are now supported with evidence-based medicine (2). Most available oral contraceptives improve cycle regularity, menstrual pain, excessive menstrual flow and acne. However, weight gain, bloating, food cravings, breast tenderness and mood alterations (especially irritability and depression and the complex of affective, behavioral and somatic symptoms of premenstrual syndrome [PMS] and the severe form of PMS, premenstrual dysphoric disorder [PMDD]) are not generally improved with the traditional oral contraceptive formulations (3). Drospirenone/ethinyl estradiol 24/4 is currently the only hormonally based contraceptive regimen with large, randomized, controlled trials demonstrating efficacy for PMDD. It has received U.S. Food and Drug Administration (FDA) indications not only for the prevention of pregnancy but also for PMDD and for moderate acne vulgaris in women who choose oral contraception for birth control (4, 5).

The pharmacologic management of premenstrual dysphoric disorder.

Premenstrual dysphoric disorder (PMDD) is characterized by physical, affective and behavioral symptoms that are linked to the luteal phase of the menstrual cycle and relieved soon after the onset of menses. The disorder is chronic and exerts a major impact on personal relationships and occupational productivity for the estimated 6% of reproductive-aged women who fulfill strict PMDD criteria and the almost 20% of women who nearly meet these criteria. There are now various pharmacologic options that have demonstrated efficacy for PMDD and two of these approaches have an approved indication for treatment from the US FDA: three selective serotonin re-uptake inhibitors; and for women who also desire hormonal contraception, a low dose oral contraceptive pill containing the progestin drospirenone, in a new dosing regimen. Due to the unique pathophysiology of the disorder, the selective serotonin re-uptake inhibitors can be effectively administered intermittently, with dosing limited to the luteal phase of the cycle (2 weeks prior to menses). In the future, new pharmacotherapy will likely evolve from research evaluating other hormonal formulations that inhibit ovulation, without simulating PMDD-like symptoms, or novel pharmacologic agents that modulate the central neurotransmission.

Drospirenone: a novel progestin.

Drospirenone is a novel progestin available in combined oral contraceptives and menopausal hormonal therapy. Similar to its parent compound spirolactone, an analog of spironolactone, drospirenone has antimineralocorticoid and antiandrogenic activity. Combined with ethinyl estradiol in oral contraceptive formulations, drospirenone-containing contraceptives have similar efficacy and safety profiles to other low-dose oral contraceptives, but seem to offer improved tolerability with regard to weight gain, mood changes, acne and treatment of a severe form of premenstrual syndrome called premenstrual dysphoric disorder. Combined with estradiol as a continuous hormone therapy regimen, the compound was shown to reduce vasomotor symptoms, maintain bone mass, have a beneficial effect on body weight and, more importantly, was shown to lower blood pressure in postmenopausal women.

Ethinyl estradiol/drospirenone for the treatment of the emotional and physical symptoms of premenstrual dysphoric disorder.

A combined oral contraceptive pill containing 20 microg of ethinyl estradiol and 3 mg of the progestin drospirenone in a novel dose regimen (24 active pills followed by 4 placebo pills), has demonstrated efficacy for the symptoms of premenstrual dysphoric disorder, a severe form of premenstrual syndrome, with an emphasis on the affective symptoms. Drospirenone has progestagenic, anti-androgenic and anti-aldosterone properties, which differ from earlier generations of progestins, and reducing the hormone pill-free interval allows for better suppression of ovarian steroid production.

Premenstrual disorders: prevalence, etiology and impact.

Millions of reproductive-age U.S. women experience premenstrual symptoms with varying degrees of severity. The large number and variety of premenstrual symptoms reported have made premenstrual disorders difficult to characterize. A number of mechanisms have been proposed to explain the etiology of premenstrual symptoms. Some women appear to have a genetic predisposition toward severe premenstrual symptoms or to have vulnerability traits that increase their risk. It has been suggested that 1 or more neurotransmitters and/or neurohormonal systems in certain women may have an abnormal response to normal fluctuations in gonadal hormones across the menstrual cycle. Premenstrual disorders can have a significant negative impact on a woman's quality of life and work productivity.